A. Field of the Invention
The invention relates generally to a fibrin-based hemostatic agent suitable for both civilian and military use.
B. Description of the Related Art
Fibrinogen is a soluble protein found in the blood plasma of all vertebrates. When fibrinogen is acted upon by thrombin, a protein enzyme, it is converted into fibrin monomer. The coagulation cascade, of which fibrinogen is a central component, is the physiological response to wounds and vascular insult. It is effective for treatment of hemorrhage, burns, skin grafts, spinal injuries and cartilage repair.
Therapeutic compositions of naturally-derived fibrin sealants and agents contain human fibrinogen derived, or pooled, from multiple human donors, have been disclosed. Tissue adhesive preparations of this type usually consist of a fibrinogen solution containing Factor XIII, some additional proteins, such as fibronectin and albumin, and active or nonactive additions. A thrombin solution, which may contain calcium ions, typically is provided, or the preparation may rely on thrombin provided from the tissue area to be bonded itself. These solutions are commercially available in the form of either deep-frozen solutions or lyophilisate due to their lack of stability as liquid aqueous solutions. The products typically are packaged in the form of kits, which include the protein ingredients, means to prepare the solutions, and means to utilize the solutions.
Although medically superior in certain aspects, the overall use of fibrin has been limited due to several shortcomings. Because of the risk of viral disease such as HIV, hepatitis B and C, and BSE (bovine preparations), these compositions cannot safely be used as wound dressings, without preparation to remove pathogen contamination. Furthermore, the naturally-derived product has a naturally slow cascade, and it also is unstable in response to environmental factors such as heat and shock. Fibrin-based clotting systems are donor dependent and expensive, and entail a difficult thrombin-based activation, which requires a double barrel syringe and refrigerated storage.
One proposed solution to the risks characteristic of therapeutic products derived from human plasma is the use of fibrinogen from a mammalian source other than humans. However, non-human fibrinogen can result in a severe immune response. Even highly purified bovine fibrinogen compositions which are currently available, such as those described in U.S. Pat. No. 5,330,974, still contain some foreign antigen. Moreover, while these products avoid the risks of human pathogens, they still are expensive and do not solve the stability or ease of use considerations that are characteristic of the human-derived products.
U.S. Pat. No. 5,464,471 describes an improvement in the design of fibrin tissue adhesives which eliminates solution preparation and mixing time as well as the risk of viral transmission and severe immunologic response. The tissue adhesive uses genetically engineered fibrin monomers rather than fibrinogen to avoid the time and constraints of preparing and pre-mixing ingredients, as well as any risk of viral transmission. It is stated that this allows the product to be lyophilized from a single solution containing all of its constituents, including thrombin. Consequently, the agent is available as a dry powder which is activated upon blood contact producing effective hemostasis and subsequent adhesion.
Various synthetic pressure dressings have been designed that can clot severe bleeding within seconds of being applied. These dressings include QuikClot®, which is made with inorganic zeolite granules. In use, it forms a molecular sieve that traps molecules in a molecular “cage” and holds the trapped species by forming hydrogen bonds. The bond formation generates heat, and can produce secondary burns. This has been a drawback in the QuikClot® product. Newer versions of the product are partially prehydrated sponges and generate less heat, but have a slower clotting speed.
Another pressure dressing is HemCon®, which is made with chitosan (an extract from shrimp shells). HemCon® does not cause secondary burn injuries and is easier to remove than the granular form of QC. However, it is more expensive than QuikClot® and is not a natural component of the coagulation cascade.
Current methods and materials do not provide adequate emergency combat care to staunch blood flow and restore hemostasis. The need exists for a fibrin-based, rapid clot, thermally stable, easily applicable hemostatic agent that is sufficiently cost effective to be deployed with each and every war fighter in the field. Furthermore, a need exists for a technology that is applicable for both intra- and extracorporeal use, and that has several platforms of use, such as powders, sponges, sealants, films, foams, and bandages. The present invention satisfies these needs.